Long-term, efficient inhibition of microRNA function in mice using rAAV vectors
Gene Therapy Center; Department of Microbiology and Physiology Systems; Department of Biochemistry and Molecular Pharmacology; Mouse Phenotyping Center; Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology; Department of Pediatrics
Dependovirus; Genetic Vectors; MicroRNAs; Dyslipidemias
Allergy and Immunology | Nutritional and Metabolic Diseases | Pediatrics | Respiratory Tract Diseases
Understanding the function of individual microRNA (miRNA) species in mice would require the production of hundreds of loss-of-function strains. To accelerate analysis of miRNA biology in mammals, we combined recombinant adeno-associated virus (rAAV) vectors with miRNA 'tough decoys' (TuDs) to inhibit specific miRNAs. Intravenous injection of rAAV9 expressing anti-miR-122 or anti-let-7 TuDs depleted the corresponding miRNA and increased its mRNA targets. rAAV producing anti-miR-122 TuD but not anti-let-7 TuD reduced serum cholesterol by >30% for 25 weeks in wild-type mice. High-throughput sequencing of liver miRNAs from the treated mice confirmed that the targeted miRNAs were depleted and revealed that TuDs induced miRNA tailing and trimming in vivo. rAAV-mediated miRNA inhibition thus provides a simple way to study miRNA function in adult mammals and a potential therapy for dyslipidemia and other diseases caused by miRNA deregulation.
DOI of Published Version
Nat Methods. 2012 Mar 4;9(4):403-9. doi: 10.1038/nmeth.1903. Link to article on publisher's site
Xie J, Ameres SL, Friedline RH, Hung J, Zhang Y, Xie Q, Zhong L, Su Q, He R, Li M, Li H, Mu X, Zhang H, Broderick JA, Kim JK, Weng Z, Flotte TR, Zamore PD, Gao G. (2012). Long-term, efficient inhibition of microRNA function in mice using rAAV vectors. Pulmonary and Allergy. https://doi.org/10.1038/nmeth.1903. Retrieved from https://escholarship.umassmed.edu/peds_pulmonary/69